Calvert Formula Research Articles

Carboplatin dosing in obese patients.

The study aimed to: 1) Describe the carboplatin dosing criteria in obese patients in routine clinical practicein a general university hospital. 2) Evaluate toxicity based on the dosing criterion used. 3) Assess effectiveness in major diagnoses according to the dosing criterion employed. An observational, retrospective, descriptive study, including all obese patients (BMI ≥ 30 kg/m2) who started carboplatin treatment between 1st January 2012 and 31st January 2015. Data on patient characteristics, disease and treatment were collected. As a result variables were collected: carboplatin dosing methods, dosage criteria, alternative dosing approaches, treatment delays, dose reductions, relative dose intensity, adverse reactions and severity (CTCAE v. 4.0) as well as overall survival and progressive free survival for major diagnoses. 1) Carboplatin dosing at the centre used Calvert's formula for calculating AUC and Cockcroft-Gault's formula for estimating glomerular filtration rate. 2) Cockcroft-Gault's formula employed actual body weight and ideal adjusted body weight in similar proportions. 3) The ideal adjusted body weight was more commonly used in patients with higher obesity and diabetes. 4) In the general population, the developmental trend of toxicity during treatment was greater in the group dosed by actual body weight, reaching significant differences in thrombopenia, neutropenia, GOT elevation, hyporexia and myalgias. 5) Major diagnoses in the present study were ovarian cancer and non-small cell lung cancer. The effectiveness in terms of overall survival and progression-free survival, comparing the groups dosed by actual body weight and ideal adjusted body weight within each pathology did not show statistically significant differences.

High-grade serous ovarian carcinoma in a patient with end-stage renal disease

Introduction. Ovarian cancer, being one of the most common gynecologic cancers, has the highest mortality rate. The gold standard for the treatment of patients with advanced ovarian cancer, along with angiogenesis inhibitors applied in certain advanced stages, is cytoreductive surgery, followed by chemotherapy (CHT). The use of chemotherapeutic agents in hemodialysis (HD) patients has some specificities and limitations, and no CHT guidelines exist for treating those patients. Case report. We present a 45-year-old female patient with end-stage renal disease undergoing HD treatment. Abdominal and pelvic magnetic resonance imaging showed a multicystic mass with a total diameter of 93 ? 115 ? 168 mm in the right ovary and two subcapsular lesions in the VI segment of the liver with a diameter of 22 ? 14 mm and 9 mm (stage IVb ovarian cancer). The serum level of the tumor marker cancer antigen 125 (CA-125) was 93 U/mL. A total hysterectomy with bilateral salpingo-oophorectomy and infracolic omentectomy was performed. Histopathological analysis of the surgical specimen confirmed high-grade serous ovarian adenocarcinoma, FIGO stage IVb. After surgery, she was treated with carboplatin and paclitaxel combination CHT, determining the dose of carboplatin according to the Calvert formula and initiating HD within 20 hrs of infusion. Two years after the diagnosis was made, the presented patient is in good condition. Conclusion. HD patients can be treated with a combination CHT regimen of carboplatin and paclitaxel, determining the dose of carboplatin according to the Calvert formula and initiating HD within 20 hrs from the end of the chemotherapeutic infusion.

Adjustment of creatinine clearance for carboplatin dosing in Calvert's formula and clinical efficacy for lung cancer.

The Cockcroft-Gault formula is commonly used as a substitute for glomerular filtration rate (GFR) in Calvert's formula for carboplatin dosing, where adjusting serum creatinine measured using the enzymatic method with 0.2 mg/dL has been suggested in Japan. However, the effects of these adjustments on efficacy in patients with non-small-cell lung cancer remain unknown. We conducted a post hoc analysis of the PREDICT1 study (CJLSG1201), a multicenter prospective observational trial of carboplatin-pemetrexed. Glomerular filtration rate values in Calvert's formula were back-calculated from the administered dosages of carboplatin and the reported value of the target area under the curve. We estimated the serum creatinine adjustments and divided the patients into crude and adjusted groups. Patients in the crude group (N = 169) demonstrated similar efficacy to those in the adjusted group (N = 104) in progression-free survival (PFS) and overall survival (OS) (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.76-1.35; p = 0.916 vs. HR, 0.87; 95% CI, 0.65-1.17; p = 0.363), with higher grade 3-4 hematologic toxicity. Among patients aged ≥75 years, the crude group (N = 47) showed superior efficacy compared with the adjusted group (N = 17) in PFS and OS (HR, 0.37; 95% CI, 0.20-0.69; p = 0.002 vs. HR, 0.43; 95% CI, 0.23-0.82; p = 0.010). Serum creatinine adjustment may be associated with similar efficacy compared to the crude serum creatinine value. In older patients, the adjustment should be cautiously applied owing to the potential for reduced efficacy.

Optimizing carboplatin dosing by an improved prediction of carboplatin clearance using a CT-enhanced estimate of renal function.

Carboplatin is generally dosed based on a modified Calvert formula, in which the Cockcroft-Gault-based creatinine clearance (CRCL) is used as proxy for the glomerular filtration rate (GFR). The Cockcroft-Gault formula (CG) overpredicts CRCL in patients with an aberrant body composition. The CT-enhanced estimate of RenAl FuncTion (CRAFT) was developed to compensate for this overprediction. We aimed to evaluate whether carboplatin clearance is better predicted by CRCL based on the CRAFT compared to the CG. Data of four previously conducted trials was used. The CRAFT was divided by serum creatinine to derive CRCL. The difference between CRAFT- and CG-based CRCL was assessed by population pharmacokinetic modelling. Furthermore, the difference in calculated carboplatin dose was assessed in a heterogeneous dataset. In total, 108 patients were included in the analysis. Addition of the CRAFT- and CG-based CRCL as covariate on carboplatin clearance led, respectively, to an improved model fit with a 26-point drop in objective function value and a worsened model fit with an increase of 8 points. In 19 subjects with serum creatinine <50 μmol/L, the calculated carboplatin dose was 233 mg higher using the CG. Carboplatin clearance is better predicted by CRAFT vs. CG-based CRCL. In subjects with low serum creatinine, the calculated carboplatin dose using CG exceeds the dose using CRAFT, which might explain the need for dose capping when using the CG. Therefore, the CRAFT might be an alternative for dose capping while still dosing accurately.

The impact of clinical equations on carboplatin dosing: A systematic review to determine appropriate dosing of carboplatin in adult cancer patients.

e15005 Background: The Calvert formula is used to estimate the carboplatin dose needed to achieve the desired Area Under the Curve (AUC) despite little consensus on which estimated Glomerular Filtration Rate (eGFR) equation best reflects renal clearance. Cockcroft-Gault (CG) is often used when calculating estimated Creatinine Clearance (CrCl) for the Calvert formula. Equations like Modification of Diet in Renal Disease or CKD-EPI (based on serum creatinine (SrCr) or cystatin C), take into account parameters such as race, gender, weight. We compared several publications to determine the most effective dosing strategy for carboplatin. Methods: Utilizing PubMed, 19 articles were found with the keywords “carboplatin, dosing, eGFR, measure GFR, creatinine clearance, muscle mass.” Our inclusion criteria consisted of being published within the last 10 years, included carboplatin dosing, and evaluated either measured GFR, measured CrCl, carboplatin clearance or toxicities caused by carboplatin. Studies not meeting these parameters were excluded. Of the 19 articles, 11 articles were identified regarding the accuracy of eGFR and its effects on carboplatin dosing and/or dose limiting toxicities. An extensive literature review of each article was used to find a consensus among the clinical equations used in carboplatin dosing. Results: There remains no consensus on the most accurate eGFR equation. Eight studies evaluated accuracy of varying equations in estimating GFR, creatinine clearance or carboplatin clearance. Two studies created new equations (one measuring GFR and the other measuring CrCl) and compared them to current equations for accuracy. Ultimately, only two studies were in agreement that CKD-EPI was the most viable option when GFR uses SrCr. Based on four studies, CG is an inadequate measurement of eGFR. CG ranked low due to a high mean percent error when compared to measured GFR, indicating a larger discrepancy between measured GFR and the estimated value of CG, as compared to other equations. Three of the studies evaluated for a correlation in skeletal muscle mass and hematological toxicities, indicating that changes in muscle mass could correlate with hematological toxicities. One small study developed a new equation based on muscle mass and SrCr and showed positive results for accuracy when compared to measure CrCl. Conclusions: Although a definitive equation to estimate renal clearance could not be established, equations like CG have limited accuracy due to race, weight, age, and gender. The single study that utilized muscle mass demonstrated the most promise and presents a better option for patients, particularly when muscle mass changes over time. Other studies illustrated that muscle mass is significantly correlated with carboplatin toxicity and should be considered for future studies to determine the safest method for dosing carboplatin.

Association between Area under the Curve Estimated from Carboplatin Dose and Incidence of Severe Thrombocytopenia in Patients with Non-Hodgkin's Lymphoma on DeVIC Therapy.

The degrees of adverse effects with carboplatin (CBDCA) are influenced by interindividual differences in the area under the curve (AUC), whereas renal function is not considered in the CBDCA dose design for dexamethasone, etoposide, ifosfamide, and CBDCA (DeVIC) therapy. We conducted this study to evaluate the association between the AUC and incidence of severe thrombocytopenia in patients treated with DeVIC with or without rituximab (DeVIC ± R). We retrospectively analyzed clinical data for 36 patients with non-Hodgkin's lymphoma who received DeVIC ± R between May 2013 and January 2021 at the National Hospital Organization Hokkaido Cancer Center. The AUC of CBDCA (AUCactual) was calculated backward using a variant of the Calvert formula. The median AUCactual was 4.6 (interquartile range: 4.3-5.3) min mg/mL and AUCactual was negatively correlated with the nadir platelet count (r = -0.45; P < 0.01). Multivariate analysis showed that AUCactual ≥ 4.3 versus < 4.3 was an independent factor predictive of severe thrombocytopenia (odds ratio: 19.3, and 95% confidence interval: 1.45-258; P = 0.02). This study suggests that the CBDCA dosing design considering renal function can reduce the risk of severe thrombocytopenia in DeVIC ± R therapy.

Simultaneous Integrated Boost vs. Routine IMRT in Limited-Stage Small-Cell Lung Cancer: An Open-Label, Non-Inferiority, Randomized, Phase 3 Trial—Interim Analysis

<h3>Purpose/Objective(s)</h3> Simultaneous integrated boost radiation technique in limited-stage small cell lung cancer is lack of evidence. This prospective study aims to evaluate whether the simultaneous integrated boost is as efficacious and safe as conventional fractionated radiotherapy. <h3>Materials/Methods</h3> This randomized, non-inferiority, open-label, phase 3 study was done in a single institution in China. Patients aged 18–70 years who was diagnosed with treatment-naïve and confirmed limited-stage SCLC were eligible. All participants received 4-6 courses of intravenous cisplatin 75 mg/m² or carboplatin (area under the curve 5–6 mg/mL × min, Calvert's formula) on day 1 and intravenous etoposide 100 mg/m² on days 1–3 every 3 weeks. Participants were randomly assigned (1:1) stratifying for the timing of thoracic radiation therapy to receive simultaneous integrated boost radiotherapy (PGTV 60.2Gy/2.15Gy/28F, PTV 50.4Gy/1.8Gy/28F) or conventional fractionated radiotherapy (PTV 60Gy/2Gy/30F) to the primary lung tumor and CT positive lymph node metastases. Responders were offered prophylactic cranial irradiation of 25Gy/2.5Gy/10F.The primary endpoint was 2-year progression-free survival, the secondary endpoints were 2-year overall survival, 2-year local-regional recurrence-free survival and toxicity. <h3>Results</h3> Between February 2017, and July 2019, 231 patients were enrolled. We analyzed 216 patients whose follow-up time was more than 2 years or who had died, among which 106 patients in the conventional fractionated radiotherapy group,110 patients in the SIB group. The 2-year progression-free survival rates were 45.2% vs 38.3% and the median progression-free survival was 18 months (95%CI:9.06-26.39) in the conventional fractionated radiotherapy group versus 17 months(95%CI:11.47-22.53) in the SIB group (P=0.2, HR 1.22,95%CI:0.87-1.72). The 2-year overall survival rates were 73.5% VS 60.9% (P=0.14, HR 1.35,95%CI:0.90-2.04). The 2-year local-regional recurrence-free survival rates were 68.7% VS 69.9% (P = 1.0, HR = 0.98, 95% CI = 0.62-1.56). The most common grade 3–4 adverse events were myelosuppression (21.7% vs 15.4%, P = 0.83), radiation pneumonitis (4.7% vs 2.7%, P = 0.44), radiation esophagitis (3.8% vs 1.8%, P = 0.51). <h3>Conclusion</h3> Simultaneous integrated boost radiotherapy was non-inferior to and had similar toxicities to conventional fractionated radiotherapy in patients with limited-stage small cell lung cancer. Further enrollment and follow-up are warranted to confirm these findings in this ongoing trial. This trial is registered at ClinicalTrials.gov, NCT04500145.

Survey of chemotherapy-induced nausea and vomiting in patients with urothelial carcinoma.

Chemotherapy-induced nausea and vomiting (CINV) can cause anorexia, weight loss and deterioration of patient quality of life. It is one of the most unpleasant adverse effects of chemotherapy treatment regimens. For the optimal treatment of gastrointestinal symptoms during urothelial carcinoma chemotherapy, the present study investigated the association between gastrointestinal symptoms and therapeutic effects of gemcitabine plus platinum [cisplatin (GC) or carboplatin (GCa)] therapies. The incidence and frequency of nausea/vomiting with GC split therapy (gemcitabine, 1,000 mg/m2 on days 1 and 8; split-dose cisplatin, 35 mg/m2 on days 1 and 8; 21-day schedule) and GCa therapy [gemcitabine, 750-1,000 mg/m2 on days 1, 8 and 15; carboplatin, area under the blood concentration-time curve=5 mg min/ml (Calvert formula) on day 2; 28-day schedule] were lower compared with those of GC therapy (gemcitabine, 1,000 mg/m2 on days 1, 8 and 15; single-dose cisplatin 70 mg/m2 on day 2; 28-day schedule). However, no differences in therapeutic outcomes were observed among therapies. GCa therapy, regardless of renal function, and GC split therapy demonstrated significant increases compared with GC therapy in alleviating gastrointestinal symptoms associated with cancer chemotherapy in patients with urothelial carcinoma. Overall, these results suggested that split-dose cisplatin administration or the use of carboplatin instead of cisplatin may be useful in patients who experience CINV without compromising treatment effectiveness.

R-DHA-Oxaliplatin before Autologous Stem Cell Transplantation Prolongs PFS and OS As Compared to R-DHA-Carboplatin and R-DHA-Cisplatin in Patients with Mantle Cell Lymphoma, a Subgroup Analysis of the LyMa Trial

BACKGROUND. The LyMA (ClinicalTrials.gov, NCT00921414) trial is a prospective international randomized phase III trial that investigated Rituximab maintenance (RM) after autologous-stem cell transplantation (ASCT) in young previously untreated mantle cell lymphoma (MCL) patients (Le Gouill et al., in press, 2017). Patients were included at diagnosis (<66y; stage >I) and induction immuno-chemotherapy consisted of 4 courses of R-DHAP-21 (Rituximab, Dexamethasone, High-dose cytarabine, Platinum salt) followed by ASCT consolidation. The conditioning regimen for ASCT was R-BEAM. Patients in response after ASCT were randomized (1:1) between RM or observation. 299 patients (<66y) were included of whom 240 were randomly assigned to RM or observation after ASCT. Median follow-up from randomization after ASCT was 50.2 (46.4-54.2) months. The final analysis demonstrates that RM is superior to observation with respect of EFS, PFS and OS. For induction with R-DHAP, local investigators were free to choose between cisplatin (continuous infusion cisplatin 100 mg/m2 over 24 h on day 1; DHA-Cis), carboplatin (with AUC = 5 mg/ml.min ; target Area Under the concentration vs. time Curve using the Calvert formula ; DHA-Ca) or oxaliplatin (130 mg/m² on day 1 ; DHA-Ox).METHODS. In the present analysis, we investigated the prognostic impact on PFS and OS of the nature of platinum salt used in the R-DHAP regimen. The intention-to-treat (ITT) analysis includes all patients who have received at least one course of R-DHAP (n=298; data missing in one patient) and per protocol analysis (PP) includes all patients who have received the same platinum salt during induction phase (n=227).RESULTS. Cisplatin, Carboplatin and oxaliplatin were used at course 1 in 184, 76 and 38 patients, respectively. Patients' characteristics at diagnosis (including MIPI) and randomization arm (RM or observation) were well balanced between the 3 groups. Twenty-seven (15%) and 38 (21%) out of 184 patients who received cisplatin from course 1 switched to carboplatin and oxaliplatin because of toxicity, respectively. In contrast, only one patient with DHA-Ca switched to DHACis and one patient with R-DHAOx switched to R-DHACa. All cases of renal failure during induction (n=8) occurred in the R-DHACis group. PFS and OS in both ITT and PP were identical in the R-DHACis and R-DHACa groups while there was a trend in favor of R-DHAOx in both PFS (p=0.092 in ITT and 0.0675 in PP) and OS (p= 0.013 in ITT and p= 0.0859 in PP). Because patients' outcome was identical with R-DHACa and R-DHACis, both groups were combined in one group (R-DHACa/DHACis) and then compared to R-DHAOx. In ITT, the 4y PFS and OS in the R-DHAOx vs R-DHACis/Ca were 86.5% (95%CI; 70.5 to 94.1) vs 65% (95%CI; 58.8 to 70.6) and 92% (95%CI; 77.1 to 97.3) vs 75.9% (95%CI; 70.1 to 80.7), respectively. In ITT, patients with R-DHAOx have a better PFS (HR=0.438; 95%CI, 0.204-0.944; p=0.035) and OS (HR=0.373; 95%CI, 0.136-1.023; p=0.0554) as compared to patients with R-DHACa/DHACis . Similar results were reached in the PP analysis: PFS (HR=0.414; 95%CI, 0.191-0.899; p=0.0257) and OS (HR=0.347; 95%CI, 0.126-0.959; p=0.0412). In multivariate analysis (with MIPI), R-DHAOx was independent prognostic marker for PFS and OS.Conclusion. The present analysis shows for the first time that R-DHAOx is a better induction regimen than R-DHACa and R-DHACis in MCL patients and strongly suggests that platinium salt are critical (and not only high dose AraC) in the R-DHAP regimen. Our finding may also have a major impact in other forms of lymphoma where R-DHAP is frequently used as a standard salvage therapy. DisclosuresLe Gouill:Roche: Consultancy, Honoraria, Research Funding; janssen: Consultancy, Honoraria; servier: Consultancy, Honoraria, Research Funding; bayer: Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Research Funding. Thieblemont:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Ribrag:BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Pharmamar: Consultancy; Esai: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel, accommodation, expenses; ArgenX: Research Funding. Jourdan:NOVARTIS: Consultancy, Honoraria. Delarue:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Salles:morphosys: Consultancy, Honoraria; BMS: Consultancy; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Tilly:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria. Lamy:Roche: Consultancy, Honoraria.

Effect of Obesity on Hematotoxicity Induced by Carboplatin and Paclitaxel Combination Therapy in Patients with Gynecological Cancer.

Despite in vivo studies suggesting that obesity increases carboplatin (CBDCA) bone marrow toxicity, the American Society of Clinical Oncology recommends that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer. Accordingly, the present study retrospectively investigated the effect of body mass index (BMI) on bone marrow toxicity in patients with gynecological cancer who underwent paclitaxel and carboplatin (TC) therapy after eliminating the effect of the target area under the curve (AUC). Risk factors for CBDCA bone marrow toxicity were also identified. A total of 110 patients with primary gynecological cancer or gynecological cancer of unknown primary origin who underwent TC therapy with a target AUC of 5-6 were included herein. Patients with a BMI of ≥25 and <25 kg/m2 were assigned to the obesity and control groups, respectively, and evaluated according to changes in hematological test values (platelet, white blood cell, and hemoglobin counts) starting from initial TC therapy administration until 21 d after the second treatment course. The obesity group had a significantly higher thrombocytopenia rate than the control group. Risk factors for thrombocytopenia ≥ grade 2 included BMI ≥25 kg/m2. Among patients with primary gynecological cancer or gynecological cancer of unknown primary origin who had a BMI of ≥25 kg/m2, those receiving CBDCA may be at increased risk for thrombocytopenia ≥ grade 2 when the dosage is calculated using the Calvert formula with the creatinine clearance level.

Inability of Current Dosing to Achieve Carboplatin Therapeutic Targets in People with Advanced Non-Small Cell Lung Cancer: Impact of Systemic Inflammation on Carboplatin Exposure and Clinical Outcomes.

The presence of elevated systemic inflammation in people with advanced non-small cell lung cancer (NSCLC) is associated with significantly shorter survival following carboplatin-based chemotherapy. This study investigated whether novel factors, such as systemic inflammation [platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR)], impact carboplatin pharmacokinetics and drug utilisation. The study also examined the ability of current and alternate dosing regimens to meet therapeutic targets. Seventy-two people with advanced NSCLC treated with carboplatin-based (460-1050 mg) doublet chemotherapy were recruited and pharmacokinetic data (n = 61) were analysed using non-linear mixed modelling. Covariate analysis was performed to investigate the impact of standard and novel patient characteristics of carboplatin pharmacokinetics. A Monte Carlo simulation of 100,000 representative NSCLC patients evaluated the ability of the Calvert formula and novel dosing strategies to achieve the targeted therapeutic range. The associations between systemic inflammation and chemotherapy drug utilisation (cycles received, relative dose intensity (RDI) and second-line uptake) and clinical endpoints were also investigated in the pharmacokinetic cohort, and two independent cohorts of people with advanced NSCLC from the Chemotherapy Dosing in Cancer-Related Inflammation (CDCRI) databasethat were administered carboplatin-paclitaxel (n = 37) or carboplatin-gemcitabine (n = 358). In all cohorts, 25-53% of people had elevated systemic inflammation (NLR > 5 or PLR > 300). In the pharmacokinetic cohort, no patients achieved the desired therapeutic target of carboplatin. Carboplatin exposure was related to renal function, as estimated using the Cockcroft-Gault formula, albumin and inflammation (NLR). In the pharmacokinetic cohort, increasing carboplatin area under the curve (AUC) correlated with greater reductions in red blood cells and haemoglobin. In this cohort, the average measured AUC of partial responders was 2.4mg·min/mL. Also in the pharmacokinetic cohort, only 12% of people with an NLR > 5 received four or more cycles of chemotherapy, compared with 62% of patients with an NLR ≤ 5 (p < 0.001). For people in the CDCRI cohort receiving carboplatin-gemcitabine, those with an NLR > 5 also received less cycles (four or more cycles, 41% vs. 60%; p < 0.01) as well as less second-line chemotherapy (46% vs. 60%; p = 0.02) compared with patients without inflammation. People in the pharmacokinetic cohort with an NLR > 5 had 12months less median survival compared with people with an NLR ≤ 5 (6.5 vs. 18months; p = 0.08). Similarly, overall survival was significantly shortened in people in the CDCRI cohort receiving carboplatin-gemcitabine with an NLR > 5 compared with those with an NLR ≤ 5 (7 vs. 12months; p < 0.001), and Cox regression analysis showed a 1.5-fold (1.3-2.1; p < 0.001) increased hazard of death associated with the increased systemic inflammation. Simulations of the newly developed model-based and Calvert dosing assessed the ability to reach this study's proposed actual target AUC of 2.2-2.6mg·min/mL. These showed current Calvert dosing was predicted to result in substantial overexposure in patients with high systemic inflammation. The newly developed model showed equivalent levels of carboplatin therapeutic target achievement across the spectrum of inflammation observed in the lung cancer population. An alternate model-based dosing strategy for carboplatin was developed and is predicted to result in consistent drug exposure across the population and improve attainment of therapeutic targets. Further studies of this new model are warranted in people with advanced NSCLC.

Formulae recently proposed to estimate renal glomerular filtration rate improve the prediction of carboplatin clearance.

While doses of carboplatin are mostly individualized according to the Calvert equation based on estimated Glomerular Filtration Rate (eGFR), there is still uncertainty regarding the best formula to predict GFR. Since Janowitz et al. recently proposed a new equation predicting GFR in cancer patients, we aimed to compare this equation to other carboplatin clearance (carboCL) predicting formulae. The actual carboCL of 491 patients was compared to predicted carboCL according to the Calvert formula using several equations to predict GFR (Janowitz, Cockcroft-Gault, MDRD, CKD-EPI, CKD-EPI with cystatin C (CKD-EPI-cysC)); and according to two others that directly predict carboCL (Chatelut and Thomas). The formulae were compared on Mean Percentage Error (MPE), Mean Absolute Percentage Error (MAPE) and percentage of patients with a prediction error above 20% (P20). The MPE, MAPE and P20 were, respectively, within the ranges - 5.2 to + 5.9%; 14.0-21.2% and 23-46%. The MAPE and P20 of Calvert-CKD-EPI-cysC were the lowest. The performance of Calvert-CKD-EPI was better than that of other creatinine-based formulae although not significantly different from the Calvert-Janowitz formula. Among formulae based on creatinine only, Calvert-CKD-EPI and Calvert-Janowitz are the least influenced by patient characteristics. Whereas CysC improves carboplatin CL prediction, the Calvert-CKD-EPI equation seems the most suitable creatinine-based formula to predict carboCL homogeneously in all subgroups of patients.

Population pharmacokinetics of carboplatin, etoposide and melphalan in children: a re-evaluation of paediatric dosing formulas for carboplatin in patients with normal or mild impairment of renal function.

Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration-time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high-risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols. Data on children receiving high-dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4mg ml-1 ·min) would be achieved using the paediatric Newell formula, modified Calvert formula and weight-based dosing. Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100ml min-1 1.73m-2 but not for those with a GFR ≥100ml min-1 1.73m-2 . A weight-based dosing regimen of 50mg kg-1 achieved the target AUC more consistently than the other formulas, regardless of renal function. GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model-based approach validates the use of weight-based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.

Analysis of carboplatin dosing in patients with a glomerular filtration rate greater than 125 mL/min: To cap or not to cap? A retrospective analysis and review.

The use of the Calvert formula to calculate carboplatin doses allows clinicians to achieve the appropriate carboplatin area under the concentration (AUC) curve. Thrombocytopenia is the dose limiting toxicity of carboplatin and optimizing AUC minimizes the risk of thrombocytopenia. Carboplatin clearance directly correlates with glomerular filtration rate (GFR) and, therefore, an accurate estimation of the renal function is needed. The Calvert formula was designed using the GFR measured by 51Cr-EDTA; however, many clinicians substitute estimated creatinine clearance (CrCl) as calculated by the Cockcroft-Gault (C-G) equation. The potential for overestimating AUC occurs when clinicians substitute actual weight in obese patients or use a low serum creatinine when calculating C-G estimated CrCl. In 2010, the National Cancer Institute recommended the GFR value within the Calvert formula should not exceed 125 mL/min, thereby capping the carboplatin dose. However, there are studies demonstrating that certain patients' actual GFR values do exceed 125 mL/min. Therefore, capping the carboplatin dose in these patients may lead to underestimating the carboplatin AUC. A single-center, retrospective study was performed to evaluate the change in platelet count pre- and post-carboplatin exposure in patients with C-G estimated CrCl greater than 125 mL/min receiving capped versus uncapped carboplatin doses. A review of carboplatin dosing strategies is also presented. This study indicated there was a larger mean difference in pre- and post-platelet count in patients receiving uncapped carboplatin compared to patients receiving capped carboplatin with no differences in toxicities. Dose capping this patient population will likely lead to a lower AUC rather than the intended AUC target, which could ultimately lead to substandard outcomes.

Variability of carboplatin dose calculation methods in Spain.

To describe and analyze the variability in carboplatin dosing strategies in Spanish hospitals. We designed a questionnaire consisting of 19 multiple-choice items structured in two sections (hospital characteristics and carboplatin dosing data). The questionnaire was sent by e-mail to all the oncology pharmacists included in the register of the Spanish Oncology Pharmacy Group (GEDEFO), and we analyzed the completed questionnaires. Response rate was 33.5% from a total of 185 pharmacy services invited to take part in the survey. All hospitals used the Calvert formula to calculate carboplatin dose with glomerular filtration rate estimated by a formula, most commonly the Cockcroft-Gault equation (80.7%). Carboplatin doses were capped in most hospitals (91.9%): 54.8% capped creatinine clearance at 125 mL/min, 11.3% capped serum creatinine, and 19.3% capped both creatinine clearance and serum creatinine. Serum creatinine cut-off values ranged from 0.36 mg/dL to 1 mg/dL. The most commonly used body weight was actual body weight for underweight, normal weight, and overweight patients. The use of adjusted ideal body weight increased in obese and especially in morbidly obese patients. The results from this survey show the variability that exists in carboplatin dose calculation methods among Spanish hospitals and the need to continue investigating to find the optimum dose calculation method and unify criteria to avoid differences between sites that can affect effectiveness and toxicity of carboplatin-containing treatments.

Toxicity and effectiveness of carboplatin in obese or overweight patients.

To evaluate the efficiency and toxicity of carboplatin using actual body weight in obese/overweight patients using the Calvert formula with Cockcroft-Gault for CrCl estimation. We evaluated the association of BMI in regards to efficiency and toxicity in a retrospective cohort study of patients who started treatment with carboplatin between 2012 and 2013. Cohorts included obese/overweight patients and normal-weight patients. Efficiency was measured by overall survival, progression-free survival and response rate. Toxicity was measured by the proportion of dose reductions and delays of chemotherapy cycles. We utilized a bivariate and multivariate analysis. Eighty-six patients were included in the study (50% obese/overweight). There was not a statistically significant difference in effectiveness and toxicity between the two groups in BMI. In the multivariate analysis, BMI not was associated with overall survival (hazard ratio: 0.95, 95% CI: 0.54-1.66, p = 0.849), progression-free survival (hazard ratio: 0.91; 95% CI: 0.54-1.54; p = 0.732), cycle delays (odds ratio (OR): 1.47, 95% CI: 0.80-2.69, p = 0.218) or carboplatin dose reductions (OR: 0.87, 95% CI: 0.35-2.15, p = 0.760). Response rate was 53.5% in both groups. In our study, obese and overweight cancer patients did not show a statistically significant difference in terms of effectiveness and toxicity compared to normal-weight cancer patients who were treated with carboplatin using their actual body weight with the Calvert formula and Cockcroft-Gault for CrCl estimation. Therefore, it was appropriate to use the actual body weight for our patients.

A randomized, controlled trial evaluating the efficacy and safety of BTH1677 in combination with bevacizumab, carboplatin, and paclitaxel in first-line treatment of advanced non-small cell lung cancer

BackgroundBTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC).MethodsPatients were randomized to the BTH1677 arm (N = 61; intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m2, Q3W) or Control arm (N = 31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed.ResultsORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; P = .2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm.ConclusionsImprovements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC.Trial registrationClinicalTrials.gov registration ID: NCT00874107. Registered 2 April 2009. First participant was enrolled on 29 September 2009.

A qualitative analysis of the impact of Carboplatin AUC 10 on physical, work functioning, and bone marrow toxicity, in patients with metastatic seminoma: A single centre experience.

558 Background: We studied the efficacy, safety and tolerability of dose dense Carboplatin AUC10 chemotherapy and explored the HRQoL (health-related quality of life) in metastatic seminoma patients receiving this regimen. Methods: 46 patients with metastatic seminoma treated with Carboplatin AUC10 were identified in our centre. Carboplatin dosing at AUC 10 was used and calculated based on Calvert formula and EDTA clearance. Treatment was administered as a single dose every 21 days for 3 or 4 cycles. Response to treatment was determined by radiological imaging and serum tumour markers. Toxicities were evaluated using the CTCAE Version 4.0. Quality of life (QOL) and long-term treatment related toxicities were assessed post treatment using a self-designed telephonic questionnaire consisting of 4 questions about toxicity, which included- hair loss, hearing impairment, days absence from work and neuropathy. Results: Clinical characteristics are as follows: median age 44 (range 26-77), 34 patients had stage II and 12 stage III seminoma; average dose of carboplatin administered was 1240mg per cycle. 4.3% patients received 2, 87% 3 and 8.7.% 4 cycles of chemotherapy. 93% of patients achieved a complete remission (CR), 4 (all stage IIC) patients required a fourth cycle of chemotherapy, 2 undergoing RPLND and 2 watchful waiting. There was no disease relapse at median follow-up of 27.5 (range 4-84) months. 13 patients (28%) had grade 3 and 2 (4%) grade 4 neutropenia, thirteen (28%) grade 3/4 thrombocytopenia, Nine (19.5%) patients required prophylactic filgrastim. Commonest non-heamatological toxicities were fatigue in 28 (50%) and nausea 14(28%) patients. QOL data was available for 35/46 (76%) of patients. 40/46 (87%) patients had no residual tinnitus, one had residual grade 1 peripheral neuropathy. Eight patients continued to work throughout treatment, 16(45%) took &lt; 5 days off work during chemotherapy, 4 took 5 to 21 days, 13 &gt; 21 days, two were retired. Conclusions: Carbo AUC10 is a safe and effective treatment. Our results suggest the lack of negative impact of Carbo AUC10 on short and intermediate QOL without compromising treatment outcomes.

Evaluation of calculating carboplatin dosage in carboplatin-pemetrexed therapy as the first-line therapy for Chinese patients with advanced lung adenocarcinoma.

ObjectiveThis study aims to explore the application of actual carboplatin in carboplatin plus pemetrexed regimen as first‐line treatment for advanced lung adenocarcinoma, and to determine the recommended dose of carboplatin for Chinese populations.MethodsFrom January 2014 to April 2016, 151 advanced lung adenocarcinoma patients who received carboplatin and pemetrexed (500 mg/m2) were included. The area under the curve (AUC) of carboplatin was back‐calculated from actual dosages using the Calvert formula. According to the median of calculated AUC, patients were divided into AUC ≥4 and <4 groups.ResultsThe median of AUC was 4 (1.8–5.5). A total of 79 patients had an AUC ≥4 and 72 patients had an AUC <4. The mean relative dose intensities of pemetrexed were 100.4% for the AUC ≥4 group, and 101.4% for <4 group. Baseline characteristic variables were balanced between the two groups, except for Eastern Cooperative Oncology Group Performance score (P = 0.044). The overall response rate (ORR) and disease control rate (DCR) were 33.8% and 90.1%, respectively, 35.4% and 86.1% for the AUC ≥4 group, and 31.9% and 94.4% for the AUC <4 group. No significant difference was observed in ORR (P = 0.650) and DCR (P = 0.086) between the two groups.ConclusionCompared with an AUC of 5 or 6, the actual clinical application of AUC was generally insufficient for Chinese populations; fortunately, therapeutic efficacy remained equal. We found that AUC <4 was as adequate as AUC ≥4 in pemetrexed plus carboplatin regimen as first‐line treatment for them.

Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study

EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75-1·12; p=0·40; median 5·4 months [95% CI 4·5-5·7] vs 4·8 months [3·9-5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83-1·04; p=0·22; median 10·9 months [95% CI 9·5-12·0] vs 9·2 months [8·7-10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36-0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46-1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78-1·40; p=0·77; and 1·02, 0·77-1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68-1·14; p=0·34; and 0·99, 0·78-1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85-1·17; p=0·97; and 1·03, 0·88-1·20; p=0·69; respectively). The most common grade 3-4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group. Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation. National Cancer Institute and Eli Lilly and Company.